Anticoagulants Overdose , and How to treatment

1. Khaled A. Alrasheedi
PharmD, Clinical Toxicologist

2. Pharmacokinetics
-Rapidly and completely absorbed after oral administration
-100% bioavailability
-High plasma protein binding capacity : 99%
-Crosses placenta  TERATOGENIC
Metabolism: By liver , through the cytochrome P-450
system.
-Half-life is 36 to 42 hours

3. Dosage and Therapeutic Monitoring
Warfarin is dosed once daily orally and titrated to
an appropriate international normalized ratio (INR) for
different conditions.
Warfarin use is monitored by measuring PT and
calculating the INR. The INR “normalizes” variations in
PT measurement due to different sensitivities of
reagents used by different laboratories.

4. Overdose
In therapeutic over medication, warfarin should be held and
indications for vitamin K administration should be reviewed in
consultation with those monitoring therapeutic dosing.
Vitamin K is indicated for those with a significantly
elevated INR that does not decrease when warfarin is
withheld or when there is evidence of hepatic synthetic
dysfunction (e.g., a significant increase in liver transaminase
concentrations or in the INR).
Fresh frozen plasma is indicated for those with active bleeding.

5. Nonbleeding Complications
Warfarin use has been implicated in the rare
development of nonhemorrhagic skin lesions ranging
from simple ecchymosis and purpura to urticaria, purple
toes, and skin necrosis.
Warfarin should be discontinued in patients who acquire
skin necrosis, and alternative anticoagulation should be
started to prevent postcapillary thrombosis.

6.  Purple toe syndrome is thought to be caused by
anticoagulant-induced bleeding into atherosclerotic
plaques releasing cholesterol crystal emboli.
Changing anticoagulation agents is thus unlikely to
prevent or reverse progression

7. SUPERWARFARINS
• They are primarily used as rodenticides and have no role in
human medical therapeutic anticoagulation.
• It is highly lipid soluble and are mostly concentrated in the
liver.
• They are 100 times more potent than warfarin.
• In overdose, their elimination half-life is weeks to months.
• up to 60 times longer than warfarin’s half-life of 35 hours.

8. Ingestion
Management of superwarfarin ingestion should be based on amount ingested
as related to circumstance of ingestion.
Patients who have ingested superwarfarins intentionally should undergo
routine decontamination and have their PT and INR monitored 24 and 48
hours after ingestion.
In the acute phase, PT and INR should be reassessed every 6 hours if
prolongation is observed.
There are no means of enhanced elimination of superwarfarins, and
multidose activated charcoal has not shown any clear benefit.
In asymptomatic patients, vitamin K1 (phytonadione) may be administered
orally at an initial dose of 5 to 15 mg/day

9. Children who ingest a small dose of a warfarin-based
rodenticide (0.01%–0.005% strength) do not need to
present to an emergency department.
If any symptoms develop, the child should have a routine
medical screening examination and PT and INR drawn.
Increases in PT and INR should be followed weekly until
a downward trend is seen.

10. Guideline For Superwarfarin Ingestion Management

11. UNFRACTIONATED HEPARIN
• UFH is only administered parenterally.
• UFH is an easily titratable medication because of its short
halflife of 1 to 2.5 hours and short duration of action of 1 to
3 hours.
• Therapeutic monitoring is through the PTT.
• The goal PTT for most vaso-occlusive events as well as
thrombosis prophylaxis when heparin is used as a single
agent is 60 to 80 seconds..

12. Overdose
• Initial treatment is discontinuation of the heparin infusion.
For patients with active bleeding requiring quick reversal,
protamine sulfate (derived from salmon sperm and testes) should
be administered.
• Protamine should be dosed as follows:
 1 mg protamine per 100 U heparin
■ Administer up to 50 mg intravenously over 10
minutes (more rapid administration may result in
hypotension or anaphylactoid reaction).
■ Half the dose of protamine for each half-life of
heparin (about 90 minutes) that has passed since
initial administration.
Watch for “rebound” hemorrhage: the half-life of protamine is
shorter than that of heparin.

13. Nonbleeding Complications
Patients who experience a drop in platelet count after
initiation of heparin therapy may have heparin-induced
thrombocytopenia (HIT).
 There are two forms of HIT:
1- HIT I is characterized by a mild and transient drop in
platelet count occurring within 2 days of heparin
administration and is usually asymptomatic, resolving
spontaneously.
2- HIT II is more serious, leading to vascular thromboses and
their complications.

14. LOW-MOLECULAR-WEIGHT HEPARINS
Pharmacokinetics
Their plasma half-life is 4 to 6 hours, with hepatic
metabolism and renal elimination.
Patients receiving LMWH therapy do not routinely
undergo therapeutic monitoring

15. If a patient does suffer an overdose and has active
bleeding, protamine should be administered using
the same guidelines as for overdose of
unfractionated heparin.
Since 1 mg of available LMWHs equals
approximately 100 anti-Xa units, 1 mg of protamine
should be given for every 1 mg of LMWH for Xa
neutralization.

16. DIRECT FACTOR XA INHIBITORS
(FONDAPARINUX)
• Representative of this emerging anticoagulant class,
fondaparinux demonstrates 100% bioavailability and is
94% bound to ATIII.
• Peak plasma levels are seen in 2 hours. The volume of
distribution (Vd) is 100 mL/kg.
• At least half of the drug is excreted unchanged in urine,
and its elimination half-life is 17 to 21 hours.
• Plasma concentration of the drug can be quantified by
serum anti–factor Xa activity when the anti–factor Xa assay
is calibrated with fondaparinux.

17. • Plasma concentration of the drug can be quantified by
serum anti–factor Xa activity when the anti–factor Xa
assay is calibrated with fondaparinux.
• No specific reversal agent has been developed yet for
fondaparinux. Because of its small volume of distribution.
• This anti–factor Xa drug is amenable to hemodialysis.

18. Direct Thrombin Inhibition
Overdose
• There is no specific melagatran or ximelagatran antagonist
in the event of an overdose.
• Patients with active hemorrhage should be administered
fresh frozen plasma for replacement of coagulation
proteins or prothrombin concentrate.
• There have been no reports of hemodialysis to remove the
drug, its small molecular weight and volume of
distribution suggest that it could be effectively
hemodialyzed.

19. Inhibition of Platelet Aggregation
(Antiplatelet Anticoagulation Therapies)
GLYCOPROTEIN IIB/IIIA INHIBITION
The gpIIb/IIIa receptor is the most prevalent cell surface
protein on platelets.
When used concomitantly with heparin, gpIIb/IIIa inhibitors
should lower the PTT goal (to a range of either 50–70 or 40–
60 seconds).
In overdose, the gpIIb/ IIIa infusion should be discontinued,
and platelets should be administered for active bleeding or a
platelet count of less than 20 × 109/L.

20. ADENOSINE DIPHOSPHATE–INDUCED PLATELET
AGGREGATION INHIBITION
Platelet activation leads to release of ADP, a soluble factor
that induces further platelet aggregation through their
recruitment and activation.
There is no therapeutic monitoring for thienopyridine
use. However, routine quantitative platelet analysis
(e.g., through a complete blood count) is indicated for
patients taking thienopyridines because they can cause
neutropenia and thrombocytopenia.

21. Overdose
Overdose of thienopyridines remains a rare occurrence
compared with other anticoagulant overdoses.
Although no thienopyridine antiplatelet reversal agent has
yet been developed, DDAVP (desmopressin) administration
may temporarily improve primary hemostasis.
Patients who overdose with clopidogrel or ticlopidine should
undergo routine decontamination with activated charcoal
and receive supportive measures.
platelet transfusion may be indicated for patients with active
hemorrhage

22. BOTANICALS WITH ANTICOAGULANT
PROPERTIES
Garlic has been shown to inhibit platelet aggregation, and
patients with previously stable INRs on warfarin have had
elevated INRs after adding garlic to their diets.
Ginger may inhibit platelet aggregation, but ingestion of up to
40 g of cooked ginger does not seem to affect platelet function.
Gingko may also affect platelet aggregation and has been
implicated in increased bleeding complications in patients
taking anticoagulants.

23. SNAKE VENOM
Almost all snakes have heparin-like substances that can
lead to coagulopathy.
All patients with snake envenomations
should have PT, PTT, INR, and fibrin split products
monitored for development of coagulopathies.